FASEB J. 2018 Sep 27:fj201801349RR. doi: 10.1096/fj.201801349RR. [Epub ahead of print]

Prostaglandin E₂ secreted by mesenchymal stem cells protects against acute liver failure via enhancing hepatocyte proliferation.

Liu Y¹, Ren H¹, Wang J¹, Yang F¹, Li J¹, Zhou Y¹, Yuan X¹, Zhu W², Shi X¹.

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs) have been recently used in clinical trials as treatment for liver diseases. However, the underlying mechanism of their effectiveness remains largely unexplored. In the present study, we confirmed that the protective effects of MSCs on mouse model of acute liver failure (ALF) were based on MSC-secreted prostaglandin (PG)E₂. Our data confirmed that MSC-secreted PGE₂ not only inhibited apoptosis but also enhanced hepatocyte proliferation, thus attenuating ALF. Moreover, Yes-associated protein (YAP) played a major role in PGE₂-triggered hepatocyte proliferation. In vitro studies showed that PGE₂ increased the expression of PGE₄ and enhanced the phosphorylation of cAMP response element binding protein, resulting in YAP activation and increased expression of YAP-related genes. Furthermore, the mammalian target of rapamycin, another major regulator of cell proliferation, was activated by YAP via suppressing phosphatase and tensin homolog through miR-29a-3p. These pathways coordinated to control cell proliferation. Collectively, MSCs could promote the recovery of ALF through PGE₂-induced hepatocyte proliferation.-Liu, Y., Ren, H., Wang, J., Yang, F., Li, J., Zhou, Y., Yuan, X., Zhu, W., Shi, X. Prostaglandin E₂ secreted by mesenchymal stem cells protects against acute liver failure via enhancing hepatocyte proliferation.